Acrylonitrile biotransformation in rats, mice, and chinese hamsters as influenced by the route of administration and by phenobarbital, SKF 525-A, cysteine, dimercaprol, or thiosulfate

Abstract

Female wistar rats, conventional albino mice, and Chinese hamsters were given a single dose of acrylonitrile, 0.5 or 0.75 mM/kg body weight. The elimination in the urine of thiocyanate, which is the main metabolite of acrylonitrile, indicated a decreasing proportion of biotransformation after oral (over 20%), intraperitoneal, or subcutaneous (2 to 5%), and intravenous (1%) administration in rats. Oral administration of acrylonitrile in hamsters and mice was also followed by higher biotransformation than intraperitoneal administration. Pretreatment of rats with phenobarbital, SKF 525 A, cysteine, or dimercaprol did not significantly influence elimination of thiocyanate in the urine after the administration of acrylonitrile, but simultaneous administration of thiosulfate significantly increased the metabolized portion of acrylonitrile given intraperitoneally in rats (almost twice) and mice (more than three times). Acrylonitrile was found to be strongly bound in blood. The study confirmed the marked effect of distribution (first-pass metabolic phenomenon) on the metabolic fate of foreign compounds. The strong acrylonitrile binding and cyanoethylation are apparently responsible for the unusually high influence of the different routes of administration on the metabolic fate of acrylonitrile. Acrylonitrile was more effectively metabolized to thiocyanate in mice than in rats after oral, intraperitoneal, and intravenous administration. A greater response of acrylonitrile to thiocyanate metabolism and a larger decrease in its acute toxicity after thiosulfate in mice than in rats indicate possible differences in the mechanism of acrylonitrile toxicity in these animals. Cyanide apparently plays a minor role in the acrylonitrile toxicity in rats, but may play quite an important one in mice.

Cytochrome P450 2E1 (CYP2E1) is Essential for Acrylonitrile Metabolism to Cyanide: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

“…This further suggested that multiple P450s may be involved in the metabolism of AN to cyanide (Mostafa et al, 1999). Earlier studies showed that inducers (phenobarbital) and inhibitors (SKF 525A) of P450 enzymes had no effect on thiocyanate excretion in animals (Gut et al, 1975). In contrast, recent studies showed that CEO-derived mercapturic acids, which are normally identified in the urine of AN-treated mice, were not detectable in the urine of CYP2E1-null mice treated with this chemical (Sumner et al, 1999;Ghanayem et al, 2000).…”

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

“…29) This is very interesting because thalidomide is virtually non-toxic to rats when given orally (PO). Intraperitoneal (IP), administration however, commonly associated with "first-pass" hepatic metabolism, 30) recapitulates the teratogenic effect of thalidomide in rats. 31) Kenyon et al 19) also showed that thalidomide given IP was effective as an anti-angiogenic agent in the mouse corneal model, whereas thalidomide given PO was inactive.…”

Biological Markers of Acute Acrylonitrile Intoxication in Rats as a Function of Dose and Time

“…This was undoubtedly due to a significant competing reaction for AN in blood, namely the reaction of AN with the sulfhydryl groups of hemoglobin. Hemoglobin is known to be highly reactive with AN (Fennell et al, 1991b;Ahmed et al, 1983;Gut et al, 1975) and this could explain the observation that covalent binding of AN to blood proteins was three to four times higher than any other tissue (Fig. 4).…”